In friend erythroleukemia, the env membrane glycoprotein (gp55) encoded by spleen focus-forming (SFFV) virus binds to erythropoietin receptors (EpoR) to stimulate erythroblastosis. Indeed, a family of murine env glycoproteins (gp70s of MCF viruses) that are related to gp55 seems to be an inherited repository of promiscuous hemopoietin agonists. Recently, we obtained evidence that mice homozygous for Fv-2r are resistant to erythroleukemia due to down-modulation of their EpoR response pathway. We propose: (1) Use cell culture assays, antisera, and mutants that we have available to thoroughly analyze the mechanism of gp55-EpoR interaction. (2) Use Fv-2r and other Friend virus resistance genes to study mechanisms whereby host genetic variation controls susceptibility to an oncogenic protein. (3) Analyze MCF gp70s as hemopoietin agonists an as mediators of virus infection. (4) Continue to analyze the mechanism whereby SFFV proviral integration immortalizes erythroblasts. (5) A CDNA encoding cell surface receptors (ecoR) for ecotropic host-range murine retroviruses has been molecularly cloned. In agreement with data for HIV, we found that infection requires a host accessory factor in addition to the virus-binding receptor protein. Identify and study this accessory factor. Also, we found that expression of ecoR in Xenopus oocytes increases facilitated transport of basic amino acids. Analyze this normal function of ecoR and its perturbation by infection. Study the metabolism and processing of ecoR and the mechanism of interference to superinfection. This program concerns pathogenic interactions of retroviral env glycoproteins with host cell receptors, a field that has become central for understanding naturally occurring human and animal retroviral diseases. The murine model has unique experimental advantages.